The major objective of this project is to define as precisely as possible the neural underpinnings of the mental retardation observed in Down syndrome. Three projects will explore the role of dysfunction in the hippocampal formation (HF) and prefrontal cortex (PFC). In the first project, subjects in two age groups (young: 6-14 yrs. and old: 30-40 yrs) will be tested on a battery of neuropsychological tasks aimed at assessing the function of these two brain regions. The specific aim of this project is to characterize the neurocognitive impairment across the life-span in DS. At the earliest age such knowledge will help in the development of targeted intervention programs. At the oldest age such knowledge should help identify those individuals most at risk for the development of early Alzheimer's disease. In the second project we will combine neuropsychological tests and neuroimaging methods, to more precisely determine the extent of dysfunction in HF and PFC. The neuroimaging paradigms will allow us to directly relate cognitive performance to both brain morphology and brain activation, thereby determining the extent to which poor performance on particular tasks coincides with abnormal structure and/or function. We will use high-resolution magnetic resonance imaging (MRI) for the structural studies, and functional MRI for the activation studies. In the third project we will constitute separate groups of high- and low-functioning adolescents with DS, and employ the same battery of neuropsychological and neuroimaging methods. Our purpose here is to determine whether low functionality in DS reflects specific impairments in target brain systems such as HF and PFC, or if it reflects non-localized brain differences, such as overall brain size. Overall, this project aims to sharpen our understanding of the neurocognitive phenotype in DS, which will foster progress in three areas: (1) this information will help create a more exact mouse model of the cognitive defect in DS; (2) the information will provide guidance to those developing intervention strategies either early in life or later, when the risk of Alzheimer's disease is significant; and (3) the information will shed light on critical differences between low- and high-functioning individuals with DS, thereby suggesting strategies for helping those individuals with the least positive prognosis.